This invention relates to a novel process for producing the under-mentioned quinazoline derivative (I) of value as a starting compound for the quinazoline derivative described in Japanese Kokai Tokkyo Koho S62-96476, and finds application in pharmaceutical industry.
This invention provides a novel and industrially improved process for producing said quinazoline derivative (I).
This invention relates to a process for producing a quinazoline derivative of the following general formula or a salt thereof: 
[wherein R1 is hydrogen or halogen; R2 is carboxy or protected carboxy; A is lower alkylene]
The present process for producing quinazoline derivative (I) or its salt is as schematically illustrated below.
Process 
[wherein R1, R2 and A are as defined above]
The inventors of this invention explored in earnest for a novel production technology for quinazoline derivative (I) and found that by reacting compound (II) with a silylating agent and then with compound (III), optionally followed by desilylation, quinazoline derivative (I) can be produced at low cost, expediently, safely, and in good yield. This invention has been developed on the basis of the above finding.
The salt of quinazoline derivative (I) according to this invention includes salts with bases, for example salts with inorganic bases, e.g. salts with alkali metals such as lithium, sodium, potassium, etc., salts with alkaline earth metals such as calcium, magnesium, etc. and ammonium salts, salts with organic bases, e.g. salts with organic amines such as triethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine, etc., and acid addition salts e.g. inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc. and organic acid addition salts such as formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate and toluenesulfonate, among others.
The various definitions given in the foregoing and following disclosures which fall within the scope of this invention are now explained and the relevant subgeneric and specific examples and comments are also given below.
The term xe2x80x9clowerxe2x80x9d as used throughout this specification means 1xcx9c6 carbon atoms unless otherwise specified.
Suitable examples of xe2x80x9chalogenxe2x80x9d includes fluorine, chlorine, bromine and iodine, for instance.
Suitable examples of xe2x80x9csubstituted silylxe2x80x9d includes mono(or di or tri)-substituted silyl.
The suitable substituent or substituents on xe2x80x9cmono (or di or tri)-substituted silylxe2x80x9d include but are not limited to lower alkyl, lower alkenyl, aryl, and ar(lower)alkyl optionally having one or more suitable substituents.
Suitable examples of said xe2x80x9clower alkylxe2x80x9d and suitable examples of the xe2x80x9clower alkyl moietyxe2x80x9d of said xe2x80x9car (lower) alkyl optionally having one or more suitable substituentsxe2x80x9d include straight-chain or branched-chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl isobutyl, tert-butyl, pentyl, hexyl, etc.
Suitable examples of said xe2x80x9clower alkenylxe2x80x9d include straight-chain or branched-chain alkenyl groups of 2xcx9c6 carbon atoms, such as vinyl, allyl, isopropenyl, 1-, 2- or 3-butenyl, 1-, 2-, 3- or 4-pentenyl, and 1-, 2-, 3-, 4- or 5-hexenyl, among others.
Suitable examples of said xe2x80x9carylxe2x80x9d and suitable examples of the xe2x80x9caryl moietyxe2x80x9d of said xe2x80x9car(lower)alkyl optionally having 1 or more suitable substituentsxe2x80x9d include phenyl and naphthyl, among others.
The xe2x80x9csuitable substituentsxe2x80x9d mentioned for xe2x80x9car(lower)alkyl optionally having 1 or more suitable substituentsxe2x80x9d include but are not limited to mono(or di or tri)-halo(lower)alkyl groups (e.g. chloromethyl, bromomethyl, chloropropyl, 1,2-dichloroethyl, 1,2-dibromoethyl, 2,2-dichloroethyl, trifluoromethyl, 1,2,2-trichloroethyl, etc.), lower alkoxy groups (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, hexyloxy, etc.), halogen atoms (e.g. fluorine, chlorine, bromine and iodine), and lower alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.).
Suitable examples of xe2x80x9cprotected carboxyxe2x80x9d include but are not limited to esterified carboxy, such as lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc. ) and mono(or di or tri)-phenyl(lower)alkoxycarbonyl optionally having nitro (e.g. benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, etc.). The more preferred, among them, are C1-C4 alkoxycarbonyl groups and the most preferred species is ethoxycarbonyl.
Suitable examples of said xe2x80x9clower alkylenexe2x80x9d include both straight-chain and branched chain groups such as, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene and propylene. The more preferred, among them, are C1-C4 alkylene groups and the most preferred species is methylene.
The process for producing quinazoline derivative (I) according to this invention is now described in detail.
Process
Quinazoline derivative (I) or its salt can be produced by reacting compound (II) or a salt thereof with a silylating agent and further with compound (III) or a salt thereof, optionally followed by desilylation. As suitable salts of compound (II), salts with the same acids as mentioned for compound (I) can be mentioned. Suitable salts of compound (III) further include salts with the same bases as mentioned for compound (I).
The silylating agent which can be used with advantage in this invention includes but is not limited to hexamethyldisilazane, trimethylchlorosilane, N,O-bis(trimethylsilyl)acetamide, hexamethyldisiloxane, N-trimethylsilylacetamide, N-methyl-N-trimethylsilylacetamide, N-trimethylsilyldimethylamine, N-trimethylsilyldiethylamine, N-trimethylsilyl-t-butylamine and N-trimethylsilylimidazole.
The reaction with the silylating agent is generally carried out in a routine solvent which does not interfere with reaction, for example toluene, tetrahydrofuran, dioxane, dichloromethane or the like. The reaction temperature is not particularly restricted but this reaction is generally conducted under cooling through heating.
The reaction with compound (III) or a salt thereof is preferably carried out in the presence of a catalyst.
The catalyst suited for this reaction includes bromides [e.g. compounds of the formula Brxe2x80x94Yxe2x80x94R3 [wherein R3 represents carboxy or protected carboxy (preferably esterified carboxy, more preferably lower alkoxycarbonyl, most preferably ethoxycarbonyl) and Y represents lower alkylene (preferably C1-C4 alkylene, most preferably methylene)],inclusive of salts thereof, compounds of the formula Brxe2x80x94R4 [wherein R4 represents substituted or unsubstituted silyl (preferably tri-substituted silyl, more preferably tri(lower)-alkylsilyl, most preferably trimethylsilyl)], inclusive of salts thereof, and compounds of the formula MX1 [wherein M represents an alkali metal (preferably sodium or lithium) and X1 represents bromo or iodo (preferably bromo)], among others]. The preferred catalyst is a compound of the formula Brxe2x80x94Yxe2x80x94R3 or a salt thereof.
The amount of the catalyst based on each mole of compound (II) or its salt is preferably about 0.1xcx9c0.5 mole, more preferably about 0.1xcx9c0.4 mole.
This reaction is carried out in the presence of a routine solvent which does not interfere with the reaction or optionally in the absence of a solvent. Preferably, however, the reaction is conducted in a solvent having a large dielectric constant (preferably, dielectric constant ∈xe2x89xa75) (such as propylene carbonate, nitrobenzene, dichlorobenzene, etc.), and the most preferred solvent is propylene carbonate.
The reaction temperature is not particularly restricted but this reaction is carried out under warming or heating, preferably at a temperature not below about 80xc2x0 C., more preferably about 90xcx9c160xc2x0 C., and most preferably about 100xcx9c150xc2x0 C.
When the reaction product is to be desilylated where necessary, this desilyation reaction can be carried out in the routine manner, for example by hydrolysis or alcoholysis.
The production of quinazoline derivative (I) or a salt thereof from compound (II) or a salt thereof in accordance with this invention can be carried out in a continuous mode without an intermediate isolation step.